Abnormal aggregation of the alpha-synuclein protein has been implicated in the pathogenesis of a number of neurodegenerative disorders. Evidence suggests that the increased expression of alpha-synuclein is correlated to disease susceptibility, as alpha-synuclein displays selective neurotoxicity in model systems. In humans, alpha-synuclein causes neurodegeneration and parkinsonism when multiple copies of the gene are inherited. Thus, one potential line of therapeutic intervention in the progression of "synucleinopathies" would be the direct attenuation of expression of alpha-synuclein using RNA interference. To develop technology amenable for translation to a clinical setting, lentiviral molecules will be created that encode both shorthairpin molecules complementary to alpha-synuclein mRNA in addition to other biomarkers and controls. The physiological consequences of attenuation of alpha-synuclein expression will be examined in a number of in vitro and in vivo systems, and the mechanism of alpha-synuclein neurotoxicity will be dissected. Finally, the effect of down-regulation of alpha-synuclein will be studied in the current rodent models of neurodegeneration to determine whether the approach might have clinical applications.